Bottom Line:
HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z).Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°.Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions.

ABSTRACTElucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.

fig11: Raman spectra of DB7z Hy2 (a) and HyA (b,c)as a functionof time of exposure to D2O vapor, ∼98% RH (a,b)and ∼11% RH (c). Peaks due to O–D stretching vibrationsemerge over the course of 72 h.

Mentions:
Hy2 and HyA were exposed todeuterium oxide vapor (∼98% and ∼11% RH) and characterizedby Raman spectroscopy at different time points (Figure 11) to investigate water dynamics in the two hydrates. The wavenumberregion 3400–2800 cm–1 is composed of peaksarising from ν(O–H), ν(N+–H),and ν(C–H) stretching vibrations; ν(O–D)stretching modes of D2O are seen between 2600 and 2300cm–1. The emergence of O–D peaks in the spectraof both hydrates on exposure to deuterium oxide vapor confirms thatD2O displaces H2O in both crystal structures.Thus, not only is the water of crystallization in HyA mobile, butwater exchange is also observed for the stoichiometric hydrate, Hy2.Water diffusion in and out of the two crystal structures is rapidand quantitative, as derived from the fact that the Raman spectraafter exposure to D2O for 72 h were indistinguishable fromfully deuterated Hy2 and HyA. DB7z also has an ammoniumproton that could exchange a hydrogen for a deuterium. To see whetherthe ammonium group had undergone exchange, the hydrate samples thathad been exposed to D2O vapor were dehydrated and comparedto the Raman spectra of the neat forms. The comparison showed thatwithin 72 h of D2O vapor exposure the ammonium group wasnot affected at all.

fig11: Raman spectra of DB7z Hy2 (a) and HyA (b,c)as a functionof time of exposure to D2O vapor, ∼98% RH (a,b)and ∼11% RH (c). Peaks due to O–D stretching vibrationsemerge over the course of 72 h.

Mentions:
Hy2 and HyA were exposed todeuterium oxide vapor (∼98% and ∼11% RH) and characterizedby Raman spectroscopy at different time points (Figure 11) to investigate water dynamics in the two hydrates. The wavenumberregion 3400–2800 cm–1 is composed of peaksarising from ν(O–H), ν(N+–H),and ν(C–H) stretching vibrations; ν(O–D)stretching modes of D2O are seen between 2600 and 2300cm–1. The emergence of O–D peaks in the spectraof both hydrates on exposure to deuterium oxide vapor confirms thatD2O displaces H2O in both crystal structures.Thus, not only is the water of crystallization in HyA mobile, butwater exchange is also observed for the stoichiometric hydrate, Hy2.Water diffusion in and out of the two crystal structures is rapidand quantitative, as derived from the fact that the Raman spectraafter exposure to D2O for 72 h were indistinguishable fromfully deuterated Hy2 and HyA. DB7z also has an ammoniumproton that could exchange a hydrogen for a deuterium. To see whetherthe ammonium group had undergone exchange, the hydrate samples thathad been exposed to D2O vapor were dehydrated and comparedto the Raman spectra of the neat forms. The comparison showed thatwithin 72 h of D2O vapor exposure the ammonium group wasnot affected at all.

Bottom Line:
HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z).Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°.Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions.

ABSTRACTElucidating the crystal structures, transformations, and thermodynamics of the two zwitterionic hydrates (Hy2 and HyA) of 3-(4-dibenzo[b,f][1,4]oxepin-11-yl-piperazin-1-yl)-2,2-dimethylpropanoic acid (DB7) rationalizes the complex interplay of temperature, water activity, and pH on the solid form stability and transformation pathways to three neutral anhydrate polymorphs (Forms I, II°, and III). HyA contains 1.29 to 1.95 molecules of water per DB7 zwitterion (DB7z). Removal of the essential water stabilizing HyA causes it to collapse to an amorphous phase, frequently concomitantly nucleating the stable anhydrate Forms I and II°. Hy2 is a stoichiometric dihydrate and the only known precursor to Form III, a high energy disordered anhydrate, with the level of disorder depending on the drying conditions. X-ray crystallography, solid state NMR, and H/D exchange experiments on highly crystalline phase pure samples obtained by exquisite control over crystallization, filtration, and drying conditions, along with computational modeling, provided a molecular level understanding of this system. The slow rates of many transformations and sensitivity of equilibria to exact conditions, arising from its varying static and dynamic disorder and water mobility in different phases, meant that characterizing DB7 hydration in terms of simplified hydrate classifications was inappropriate for developing this pharmaceutical.